MODELS FOR CYTOCHROME P-450 HYDROXYLASES

这项研究针对的是功能类似物 酶家族细胞色素P-450。这些混合功能的加氧酶 参与固醇的生物合成和代谢，在药物中 解毒，以及外源生物对有毒和 致癌产品。本研究的目的是提供 氧活化机制的分子背景 转移，以及在自杀抑制功能的作用 酶P-450。 新型金属卟啉化合物将被合成和研究 作为各种有机底物氧化的催化剂。 P-450反应循环中间阶段的类似物 会被分离，表征，然后反应化学会 被研究。 这项工作将集中在半胱氨酸硫醇的特殊作用上 异解还原裂解中的配体和激活剂 P-450反应周期中的氧气。各种电化学法 使用Flavin调解器的技术将被用来模拟这两个 P-450反应中的临界单电子转移步骤 序列。电化学、动力学测量、合成 有机化学和无机化学和一系列光谱 技术(核磁共振、红外、拉曼、MCD、穆斯堡尔谱、X-射线衍射 和EXAFS)将用于这一分子仿生研究。 血红素中心的铁原子的Ru类似物将是 在P-450化学的背景下进行准备和研究。

This research is directed towards functional analogues of the enzyme family cytochromes P-450. These mixed-function oxygenases are involved in sterol biosynthesis and metabolism, in drug detoxification, and in bioactivation of xenobiotics to toxic and carcinogenic products. The present studies are intended to provide a molecular background for the mechanisms of oxygen activation and transfer, and of suicide inhibition during the function of the enzymes P-450. Novel metalloporphyrin compounds will by synthesized and examined as catalysts for the oxygenation of various organic substrates. Analogues of ,he intermediate stages in the P-450 reaction cycle will be isolated, characterized, and then reaction chemistry will be studied. This work will focus on the special role of the cysteine mercaptide ligand and of activators in the heterolytic reductive cleavage of dioxygen during the P-450 reaction cycle. Various electrochemical techniques with flavin mediators will be used to mimic the two critical single-electron transfer steps in the P-450 reaction sequence. Electrochemistry, kinetics measurements, synthetic organic and inorganic chemistry and a range of spectroscopic techniques (1H NMR, IR, Raman, MCD, Mossbauer, X-ray diffraction and EXAFS) will be used in this molecular biomimetic research. Ruthenium analogues of the iron atoms in heme centers will be prepared and studied in the context of P-450 chemistry.